title: Reversible inhibitor of p97, DBeQ, impairs both ubiquitin-dependent and autophagic protein clearance pathways.
abstract: A specific small-molecule inhibitor of p97 would provide an important tool to investigate diverse functions of this essential ATPase associated with diverse cellular activities (AAA) ATPase and to evaluate its potential to be a therapeutic target in human disease. We carried out a high-throughput screen to identify inhibitors of p97 ATPase activity. Dual-reporter cell lines that simultaneously express p97-dependent and p97-independent proteasome substrates were used to stratify inhibitors that emerged from the screen. N2,N4-dibenzylquinazoline-2,4-diamine (DBeQ) was identified as a selective, potent, reversible, and ATP-competitive p97 inhibitor. DBeQ blocks multiple processes that have been shown by RNAi to depend on p97, including degradation of ubiquitin fusion degradation and endoplasmic reticulum-associated degradation pathway reporters, as well as autophagosome maturation. DBeQ also potently inhibits cancer cell growth and is more rapid than a proteasome inhibitor at mobilizing the executioner caspases-3 and -7. Our results provide a rationale for targeting p97 in cancer therapy.
authors.affiliation: Division of Biology, California Institute of Technology, Pasadena, CA 91125, USA. tfchou@caltech.edu
authors.forename: Tsui-Fen
authors.initials: TF
authors.lastname: Chou
authors.forename: Steve J
authors.initials: SJ
authors.lastname: Brown
authors.forename: Dmitriy
authors.initials: D
authors.lastname: Minond
authors.forename: Brian E
authors.initials: BE
authors.lastname: Nordin
authors.forename: Kelin
authors.initials: K
authors.lastname: Li
authors.forename: Amanda C
authors.initials: AC
authors.lastname: Jones
authors.forename: Peter
authors.initials: P
authors.lastname: Chase
authors.forename: Patrick R
authors.initials: PR
authors.lastname: Porubsky
authors.forename: Brian M
authors.initials: BM
authors.lastname: Stoltz
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Schoenen
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Patricelli
authors.forename: Peter
authors.initials: P
authors.lastname: Hodder
authors.forename: Hugh
authors.initials: H
authors.lastname: Rosen
authors.forename: Raymond J
authors.initials: RJ
authors.lastname: Deshaies
mesh_terms: D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001343:Autophagy / Q000187:drug effects*; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D053179:Caspase 7 / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D004721:Endoplasmic Reticulum / Q000201:enzymology* / Q000235:genetics; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism; D011799:Quinazolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D025801:Ubiquitin / Q000235:genetics / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; C558357:N2,N4-dibenzylquinazoline-2,4-diamine; D009687:Nuclear Proteins; D011799:Quinazolines; D025801:Ubiquitin; C505407:CASP3 protein, human; C505520:CASP7 protein, human; C505409:Casp3 protein, mouse; C505524:Casp7 protein, mouse; D053148:Caspase 3; D053179:Caspase 7; D046988:Proteasome Endopeptidase Complex; D000251:Adenosine Triphosphatases; C404942:p97 ATPase